Bioequivalence study of two formulations of flupirtine maleate capsules in healthy male Chinese volunteers under fasting and fed conditions

AIM: This study developed a high-performance liquid chromatography–tandem mass spectrometry method to simultaneously determine the concentrations of flupirtine and its major active metabolite D-13223 in human plasma in order to assess the bioequivalence (BE) of two flupirtine maleate capsules among healthy male Chinese volunteers under fasting and fed conditions. MATERIALS AND METHODS: There were two single-center, randomized, single-dose, open-label, laboratory-blinded, two-period, cross-over studies which included 24 healthy male Chinese volunteers under fasting and fed conditions, respectively. Plasma samples were collected prior to and up to 48 h after dosing. The concentrations of flupirtine and its major active metabolite D-13223 in plasma samples were determined by a validated method, that is, high-performance liquid chromatography coupled with a tandem mass spectrometry detector. Pharmacokinetic metrics of area from time zero to the last measurable concentration (AUC(0−t)), area under the plasma concentration–time curve from administration to infinite time (AUC(0−∞)), and C(max) were used for BE assessment. RESULTS: Forty-eight healthy volunteers who met the criteria were enrolled and completed the study. According to the observation of vital signs and laboratory measurement, no volunteers had any adverse reactions. Under fasting condition, the geometric mean ratios (90% CI) of the test/reference drug for flupirtine were 103.0% (98.1%–108.2%) for AUC(0−t), 102.9% (98.2%–107.9%) for AUC(0−∞), and 97.0% (85.9%–109.5%) for C(max). Under fed condition, the geometric mean ratios (90% CI) of the test/reference drug for flupirtine were 101.7% (98.4%–105.1%) for AUC(0−t), 101.6% (98.5%–104.8%) for AUC(0−∞), and 103.5% (94.7%–113.0%) for C(max). The difference between test and reference formulations, T(max), was not statistically significant. The 90% CIs of the test/reference AUC ratio and C(max) ratio of D-13223 were also within the acceptance range for BE both under fasting and fed conditions. CONCLUSION: The two formulations of flupirtine maleate capsule were bioequivalent (the test and the reference products) under fasting and fed conditions, and thus both can be used interchangeably in the clinical setting.